Di George syndrome 22q11.2 deletion syndrome

AGE <2 AGE 2-18 European J Ped Nov 2004

IMMUNOLOGIC FEATURES  Aplasia-Hypoplasia Thymus  Variable immunological defects ( from normal to severe combined immunodeficiency) 20-40% DGS + immunological defects are not associated with conotruncal cardiac defects

IMMUNOLOGICAL CLASSIFICATION Complete DGS Partial DGS   CD3/CD4/CD8 No T cell response to mitogens    CD45RA,TREC    TCRBV  CD3/CD4/CD8 /N proliferation tests in vitro  CD45RA,TREC  TCRBV DGS with normal T cell subset

PARTIAL DGS Frequent  T cells/ n/  proliferation test Humoral defects Autoimmunity variable therapy

Infections in 22q11.2 deletion syndrome No symptoms Recurrent respiratory infections Other infections (rare) (recurrent parotitis , papilloma virus,mastoiditi, osteomielitis)

HUMORAL DEFECTS Hypo-Hypergammaglobulinemia IgG  IgA ,  IgM  Subtypes IgG  anticorpi specific antibody response (antipneumococcal, antitetanous, antihaemofilus) Jawad 2001, Kornfeld 2000, Smith 1998, Jennery 2003, Chinen 2003

FACTORS INFLUENCING INFECTIONS IN DGS Immunodeficit/Allergy Anatomical Anomalies (ear, larinx, trachea, atresia coane) Reflux gastroaesophagus Congenital heart disease Malnutrition ORL

Autoimmune manifestation (10%) DGS e Autoimmunity Autoimmune manifestation (10%) NO CORRELATION T cell values but  T CD4+CD25+ Sullivan KE, 2002 Play a role in development of autoimmunity

AUTOIMMUNITY Autoantibody JCA Trombocytopenia (Bernard-Soulier) Hemolitic anemia Tiroiditis Raynaud Urticaria Vitiligo Psoriasis RA corea Cerebellitis? Jawad 2001, Kornfeld 2000, Smith 1998, Jennery 2003 Chinen 2003

T CELLS IN DGSp T CELL VALUES ARE DECREASED COMPARED WITH AGE MATCHED HEALTHY DONORS BUT THEY ARE NOT PREDICTIVE OF INFECTIONS Sullivan K 2001

Kinetics of the T-cell receptor CD4 and CD8 V repertoire and immune function in DGSp to determine the extent and nature of the immunodeficiency and to correlate it to clinical and immunological findings Humoral compartment by analyzing antibody response in vivo and by immunophenotyping B cell subsets in peripheral blood

SPECTRATYPING Amplification of TCRBV family by detection of different segment of CDR3

TCRBV DISTRIBUTION IN pDGS (CD4 SUBSET) % alterazioni TCRBV Pazienti

TCRBV DISTRIBUTION IN pDGS (CD8 SUBSET) % alterazioni TCRBV ID K Pazienti

Kinetics of TCRBV 13.2 (p2) T=0 6 months of age T1

TCR repertoire in 22q11.2 deletion syndrome  alterations of TCR repertoire in CD8 subset in 22q11.2 deletion syndrome patients compared to age- matched healthy controls (Sullivan 2004, Pierdominici 2003) (p=0,022) Improvement TCR repertoire distribution during follow- up  alterations of TCR repertoire in CD8 subset in DGSp with recurrent infections (trend p>0.08)  TREC values These preliminary data suggest that TCR repertoire alteration reflect altered T cell development (CD8 >CD4)

Kinetics of the T-cell receptor CD4 and CD8 V repertoire and immune function in DGSp to determine the extent and nature of the immunodeficiency and to correlate it to clinical and immunological findings Humoral compartment by analyzing antibody response in vivo and by immunophenotyping B cell subsets in peripheral blood

B CD27+ B natural effector CD27+ IgM+ IgD+ Primary response Polisaccharide antigens (pneumococcal) B CD27+ IgM-IgD- able to switch Rapid activation Class switch Higher antibody affinity somatic permutation B CD27+ are decreased in CVID, HIV , SCID-transplanted

CD27+ B CELLS in 22q11.2 DS (P<0.01) (P<0.05)

CD27+ IgM+IgD+ B CELLS in 22q11.2 DS (P<0.05) (P<0.05)

CD27+ B CELLS in 22q11.2 DS  CD27+ IgM+ IgD+ in 22q11.2 DS compared to age-matched controls (p<0.05) Decreased values of CD27 IgM+IgD+ could increased the risk of recurrent infections in these patients A COMPLETE EVALUATION OF IMMUNE FUNCTION INCLUDING IgD+ IgM+ CD27+ SUBSET AND HUMORAL COMPARTMENT SHOULD BE CONSIDERED

IMMUNOLOGICAL EVALUATIONS T CELL PHENOTYPE Proliferation Test in vitro spectratyping IgG, IgA, IgM (subtypes) Specific antibody response autoantibody B cell maturation? T B

CONCLUSION I Variability of immunological alterations and of their clinical expression does not allow easily to make a standard protocol of diagnosis and therapy in DGS Further study in a larger number of patients could contribute to select which immunological parameters influence the development of infections and autoimmune diseases

CONCLUSION II Because of the wide clinical spectrum an optimal care of these patients is best provided by a multidisciplinary team of experts in a Long-term follow-up Natural history of 22q11.2 DS

Paediatric Hospital Bambino Gesù Tor Vergata University - Rome Andrea Finocchi Patrizia Ciaffi Claudia Capponi Maria Luisa Romiti Silvia Di Cesare Rita Carsetti Paolo Rossi Paediatric Hospital Bambino Gesù Tor Vergata University - Rome

AGE< 1 Year 2-6 years 6 -18 years Cardiac defect A-Hypoplasia thymus Immunodeficiency Recurrent infections (> otitis) Autoimmunity hypocalcemia hypoparatiroidism Feeding difficulties Cleft palate Speech language impairment Developmental delay Behavioural delay Learning difficulties Others malformations Others malformations /scoliosis Dysmorphic features

VACCINATION Regular schedule it is recommended : anti-HIB antipneumococcal Immunological evaluation before measle vaccination FIRST YEAR OF LIFE

THERAPY Clinical course ATB Immunoglobulins iv